Aalborg Universitet

Guidelines for the understanding and management of pain in chronic pancreatitis

Drewes, Asbjørn M; Bouwense, Stefan A. W.; Campbell, Claudia M; Ceyhan, Güralp O;Delhaye, Myriam; Demir, Ihsan Ekin; Garg, Pramod K; van Goor, Harry; Halloran,Christopher; Isaji, Shuiji; Neoptolemos, John P; Olesen, Søren S; Palermo, Tonya A.;Pasricha, Pankaj Jay; Sheel, Andrea; Shimosegawa, Tooru; Szigethy, Eva M; Whitcomb,David C; Yadav, Dhiraj; Working group for the International (IAP – APA – JPS – EPC)Consensus Guidelines for Chronic PancreatitisPublished in:Pancreatology

DOI (link to publication from Publisher):10.1016/j.pan.2017.07.006

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Citation for published version (APA):Drewes, A. M., Bouwense, S. A. W., Campbell, C. M., Ceyhan, G. O., Delhaye, M., Demir, I. E., ... Workinggroup for the International (IAP – APA – JPS – EPC) Consensus Guidelines for Chronic Pancreatitis (2017).Guidelines for the understanding and management of pain in chronic pancreatitis. Pancreatology, 17(5), 720-731. https://doi.org/10.1016/j.pan.2017.07.006

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Pancreatology 17 (2017) 720e731

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Pancreatology

journal homepage: www.elsevier .com/locate/pan

Guidelines for the understanding and management of pain in chronicpancreatitis*

Asbjørn M. Drewes a, *, Stefan A.W. Bouwense b, Claudia M. Campbell c,Güralp O. Ceyhan d, Myriam Delhaye e, Ihsan Ekin Demir d, Pramod K. Garg f,Harry van Goor b, Christopher Halloran g, Shuiji Isaji h, John P. Neoptolemos g,Søren S. Olesen a, Tonya Palermo i, Pankaj Jay Pasricha j, Andrea Sheel g,Tooru Shimosegawa k, Eva Szigethy l, David C. Whitcomb m, Dhiraj Yadav m, for theWorking group for the International (IAP e APA e JPS e EPC) Consensus Guidelines forChronic Pancreatitisa Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmarkb Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlandsc Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, USAd Department of Surgery, Klinikum rechts der Isar, Technische Universit€at München, Munich, Germanye Department of Gastroenterology, Erasme University Hospital, Brussels, Belgiumf Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, Indiag Institute of Translational Medicine, University of Liverpool, United Kingdomh Department of Surgery, Mie University Graduate School of Medicine, Japani Seattle Children's Hospital Research Institute, Washington School of Medicine, USAj Center for Neurogastroenterology, Johns Hopkins University School of Medicine, Baltimore, USAk Department of Gastroenterology, Tohoku University Graduate School of Medicine, Japanl Visceral Inflammation and Pain Center, Division of Gastroenterology, University of Pittsburgh and UPMC, Pittsburgh, PA, USAm Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, PA, USA

a r t i c l e i n f o

Article history:Received 23 March 2017Received in revised form26 June 2017Accepted 11 July 2017Available online 13 July 2017

Keywords:Chronic pancreatitisPain treatment

* Recommendations from the Working Group forGuidelines for Chronic Pancreatitis in collaboration wation of Pancreatology, American Pancreatic AssociatioEuropean Pancreatic Club.* Corresponding author. Centre for Pancreatic Dise

ment of Gastroenterology and Hepatology, ClinicalHospital, Mølleparkvej, 9000 Aalborg, Denmark.

E-mail address: amd@rn.d (A.M. Drewes).

http://dx.doi.org/10.1016/j.pan.2017.07.0061424-3903/© 2017 IAP and EPC. Published by Elsevier

a b s t r a c t

Abdominal pain is the foremost complication of chronic pancreatitis (CP). Pain can be related to recurrentor chronic inflammation, local complications or neurogenic mechanisms with corresponding changes inthe nervous systems. Both pain intensity and the frequency of pain attacks have been shown to reducequality of life in patients with CP. Assessment of pain follows the guidelines for other types of chronicpain, where the multidimensional nature of symptom presentation is taken into consideration. Quan-titative sensory testing may be used to characterize pain, but is currently used in a research setting inadvanced laboratories.

For pain relief, current guidelines recommend a simple stepwise escalation of analgesic drugs withincreasing potency until pain relief is obtained. Abstinence from alcohol and smoking should be stronglyadvised. Pancreatic enzyme therapy and antioxidants may be helpful as initial treatment. Endoscopictreatment can be used in patients with evidence of ductal obstruction and may be combined withextracorporeal shock wave lithothripsy. The best candidates are those with distal obstruction of the mainpancreatic duct and in early stage of disease. Behavioral interventions should be part of the multidis-ciplinary approach to chronic pain management particularly when psychological impact is experienced.Surgery should be considered early and after a maximum of five endoscopic interventions. The type of

the International Consensusith the International Associ-n, Japan Pancreas Society and

ases & Mech-Sense, Depart-Institute, Aalborg University

B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

A.M. Drewes et al. / Pancreatology 17 (2017) 720e731 721

surgery depends on morphological changes of the pancreas. Long-term effects are variable, but highsuccess rates have been reported in open studies and when compared with endoscopic treatment.Finally, neurolytical interventions and neuromodulation can be considered in difficult patients.© 2017 IAP and EPC. Published by Elsevier B.V. This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

In 2016, John P Neoptolemos, David C Whitcomb and TooruShimosegawa embarked on a joint venture to produce the first trulyInternational Guidelines on chronic pancreatitis (CP) withendorsement from the four International Societies and supportfrom their respective Presidents and members in general. Althoughdifferent guidelines exist such as the recent European consensus[1], the aim was to create a fresh clinical approach to the mostimportant complications of CP; not only to assist a more pragmaticbasis for patient diagnosis and management, but also to helpaccelerate the assessment and hence the development of newertherapies. The guidelines follow a new mechanistic definition ofchronic pancreatitis and conceptual model of disease initiation andprogression [2], which has been adopted by major internationalsocieties. Producing guidelines on CP is unquestionably a consid-erable task. Therefore the core committee for the working groupdecided to divide the work into more manageable sections. Eachsection focused on the key topics of CP, which were felt wouldbenefit from consensus statements. The core committee identifiedInternational experts to ensure multidisciplinary representationfrommost regions of the world, and theywere invited to contributework to their respective areas. Calls for volunteers to participate inthe process were also circulated around the four InternationalSocieties.

Prior to the process starting, the core committees were asked tovote on their preferred system for rating the quality evidence,which would be used as the basis for the International CP guidelinerecommendations. The consensuswas in favor of adopting a GRADE(Grading of Recommendations Assessment, Development, andEvaluation) approach for topics lending themselves to evidencebased statements. The guideline development process evolved overseveral milestone meetings at subsequent society conferenceshosted throughout 2016.

The members of the Pain Management Working Group wereappointed to represent worldwide specialists in treatment ofpancreatic pain with representatives from gastroenterology,endoscopy, surgery and psychiatry/psychology. This was done toensure an appropriate balance between the different regions andspecialties in order to achieve the most comprehensive evaluationand recommendations. AMD was appointed as chairman of thegroup. First the following questions (Q) thought to be the mosturgent and clinical relevant were made and authors assigned toanswer them. These were (author initials in brackets):

Q1. What is the natural history and burden of pain in CP (inrelation to treatment)? (DY, CMC)Q2. Are there different types of pain in CP? (PJP, SSO, ES)Q3. Which methods are available to assess pancreatic pain andits response to treatment? (CMC, PJP)Q4.What is the role of smoking and alcohol on pain treatment inCP? (ES, PKG)Q5. Do enzymes and antioxidants influence pain in CP? (PKG,ES)Q6. How can analgesics be used to treat pain in CP? (SSO, AMD,ES)

Q7. Is endoscopic therapy effective for pain treatment in CP?(MD, SI, SAWB)Q8. Is ESWL effective for pain treatment in CP? (CH, MD)Q9. Are other treatments (psychological, neurolytical etc.) ofvalue for pain treatment in CP? (HvG, ES, TP)Q10. What is the optimal surgical approach to release pain inCP? (GOC, HvG, SAWB)Q11. When is the optimal time for surgery in painful CP? (GOC,IED)Q12. How to manage pain "relapse" after surgery or endoscopy?(IED, SI)Q13. What are the indications for referral to a specialist centerfor further investigation of pain (CH, DY)

The working group then provided a structured format for sys-tematic reviews for the different questions, and included in-structions on how to evaluate the level of evidence and clinicalimplications according to the GRADE guidelines, as adapted for“UpToDate” (http://www.uptodate.com/home/grading-tutorial). Inthe absence or limited availability of literature, the Pain Manage-ment Working Group decided if a recommendation would beincluded in the consensus report. The quality of evidence sup-porting the different statements was graded as (i) “high” if therewas very low probability of further research completely changingthe presented conclusions, (ii) “moderate” if further research maycompletely change the conclusions, (iii) “low” if further research islikely to change the presented conclusions completely. The term“very low” (iv) could be used if new research will most probablychange the presented conclusions completely; however, the termwas not used in the present work.

The strength of the recommendation was classed as “weak/conditional”, “strong” or “not applicable”. This took into accountthe quality of evidence, the translation of evidence into clinicalpractice, and any relevant uncertainties relating to population risk.

Finally, to gauge the level of objective support from theparticipating international expert panel, the members of the PainManagement Working Group voted using a nine-point Likert scaleon their level of agreement with the recommendations and theirGRADE score. Voting results were classified under “agreement” aseither; strong (�80% of votes were 7 or above), conditional (�65%of votes were 7 or above), and weak (<65% of votes were 7 orabove).

All authors reviewed the final manuscript to ensure the generalrelevance and applicability of the conclusions. The EuropeanPancreatic Club conference in July 2016 hosted the first milestonemeeting for the process of developing the International CP guide-lines. AMD presented the outcomes of “the Pain ManagementWorking Group” to the meeting and the work is summarized in thismanuscript.

In the present document, the recommendations are listedwith asummary of the most relevant information and references. How-ever, due toword limitsmost information could not be included andthe reader is encouraged to see the Appendix where the full textand references are found.

A.M. Drewes et al. / Pancreatology 17 (2017) 720e731722

Q1. What is the natural history and burden of pain in chronicpancreatitis?

Abdominal pain is the most frequent symptom of CP. However, theseverity, temporal nature, and natural history of pain is highlyvariable (Quality assessment: moderate; Recommendation: strong;Agreement: strong)

While variation in disease estimates exist, the prevalence of CPhas been approximated at ~50/100,000 population [3]. Abdominalpain, alone or during episode(s) of acute exacerbation of pancrea-titis, is the most common symptom. Patients typically describetheir pain as a dull, sharp or nagging sensation in the upperabdomen, which can radiate to the back, and often presents after orworsened by food intake. In natural history studies, pain wasobserved as the initial presentation in ~75% of patients [4], andpresent during the clinical course in 85e97% [4e7]. Patients withearly onset-disease and those with alcohol etiology are more likelyto have pain [4,5]. According to the burn-out hypothesis, a majorityof patients with chronic pancreatitis achieve lasting pain-free sta-tus during the clinical course [5,8]. This claim, however, has notbeen substantiated by others, mainly due to persistence of painsymptoms in a significant fraction of patients with ongoing paineven after 10 or more years of disease [9]. Naturally, CP is a majorburden for patients and both pain intensity and the frequency ofpain attacks have been shown to reduce quality of life substantially[10,11].

Q2. Are there different types of pain in CP and what does itmean for treatment?

Pain in CP remains poorly understood and inadequately correlatedwith neurobiological mechanisms. By definition, CP is characterizedby inflammation but unlike other inflammatory disorders, there is apaucity of therapeutic attempts targeting this particular aspect ofpathophysiology. On the other hand, there are striking changes instructure and function in both the peripheral and central nervoussystem in this condition, lending plausibility to a maladaptive statethat includes both neuropathic and dysfunctional pain. In theabsence of effective anti-inflammatory approaches, it is clearlyimportant to focus on the alteration of function that accompaniesthese changes in the nociceptive system as a potential therapeutictarget. (Quality assessment: low; Recommendation: strong;Agreement: strong)

An early approach to classifying pain in CP was made by Ammanet al. [8] “A-type pain” pattern was seen in patients with one ormore discrete episodes of pain interspersed with pain-free in-tervals. Slightly less than half (44%) of patients also had “B-typepain” described as persistent (i.e. daily) pain over prolonged pe-riods of time and/or closely clustered exacerbations of severe pain.A later study demonstrated that clinical outcomes were best pre-dicted when “intermittent” (about 45% of patients) versus “con-stant” pain were compared, thus echoing the earlier binaryclassification [10].

Putative neurobiological causes of pain

Inflammation: It is intuitively appealing to suggest that a sig-nificant, if not major, type of pain in CP is inflammatory in nature.Animal models have also shown that inflammatory pain in CP ismechanistically generally similar to other chronic inflammatoryconditions. The expression of numerous algogenic factors is altered

in experimental models as well as in human pancreatic specimens.Some but not all of these factors andmolecules have been shown tocorrelate with pain severity, although causation is not proven[12e14]. On the other hand, “intermittent” episodes of painobserved in patients correspond not always to a “flare” of inflam-mation. Correspondingly, in a large prospective cohort study, therewas no correlation between temporal pattern and the presence orabsence of radiological evidence of inflammation or obstructivepathology [10,15].

Neuropathy: Animal models have provided convincing evidencethat CP results in hypersensitivity of pain responses to pancreaticstimulation, associated with impressive sensitization of the pri-mary nociceptive neurons with specific electrophysiological andmolecular changes. Themodels also suggest a component of centralsensitization including potential roles for spinal glial activation anddescending inhibitory pathways [16e18]. Correspondingly, patientswith severe CP have lower pain thresholds and expanded painreferral areas than patients with moderate CP or healthy volun-teers, which many be a reflection of spinal sensitization [19,20].Alterations in descending inhibitory influences on spinal nocicep-tive neurons have also been shown in humans [19e22]. Finally,electroencephalographic and imaging findings in patients with CPsimilarly show functional changes suggesting a maladaptive painresponse [20,23e26].

Q3. Which methods are available to assess pancreatic pain andits response to treatment?

Assessment of pain in CP follows the guidelines for other types ofchronic pain, where the multidimensional nature of symptompresentation is taken into consideration. Only a few instrumentshave been validated for subjective pain assessment in CP; however,several appropriate measures exist despite not being rigorouslyvalidated in this population. (Quality assessment: moderate;Recommendation: strong; Agreement: strong)

Subjective verbal reports

One-dimensional scales (usually pain intensity)One-dimension scales assess a single element of pain, and allow

for a simple and fast method for patients to self-report the sub-jectively experienced intensity of their pain, but can oversimplifythe pain experience [27].These scales use numeric (often 0e10),verbal or visual descriptors to quantify pain or the degree of painrelief. Numerical scales, such as the visual analogue scale (VAS), arecommonly applied to assess the intensity of pain in CP patients, butshould be combined with a standardized registration of the painpattern in time [10].

Multidimensional scalesMultidimensional scales measure several of the above over-

viewed aspects of pain, including its intensity, nature and location,and in some cases, pain's impact on mood or activity level. Acommonly used measure in CP, the Izbicki pain score was devel-oped to capture some of the aforementioned dimensions of painand provide a surrogate score [28]. It has, however, never beenstrictly validated in patients with CP. The Brief Pain Inventory (BPI)is commonly used with chronic pain patients and validated in CP. Itquantifies intensity as well as pain's interference in mood, ability towork etc., and correlates with quality of life in CP patients [11]. TheMcGill Pain Questionnaire is another commonly used survey thatassesses three aspects of the pain experience, including sensory,affective, and evaluative dimensions and likely a more appropriatepain assessment measure in CP patients than unidimensional

A.M. Drewes et al. / Pancreatology 17 (2017) 720e731 723

numeric scales alone [29].

Quantitative sensory testing (QST)

Pain sensitivity can be reliably assessed and quantified in thelaboratory using quantitative sensory testing (QST) [30]. Thesecalibrated and standardized methods for delivering noxious stimuliunder controlled conditions [31] are reflective of clinical conditions,as subjects who rate QST stimuli as most painful [32,33], or showheightened central sensitization [34,35] report the most frequent,disabling clinical pain. Dynamic QST techniques have the potentialto more directly assess CNS pain-modulatory processes [36]. QST isfrequently employed to evaluate treatment responses among CPpatients. For example, pregabalin inhibited central sensitization[37], and oxycodone was found to be more effective than morphineon visceral pain in patients with CP [38].

Q4. What is the role of smoking and alcohol on paintreatment in CP

Abstinence from alcohol and smoking, in addition to adequatetreatment, should be strongly advised in patients with CP (Qualityassessment: moderate (alcohol) to weak (smoking); Recommen-dation: strong; Agreement: strong)

Alcohol: High alcohol intake is a risk factor for acute and chronicpancreatitis [39], and abstinence from alcohol is associated withreduction in frequency of recurrence of pancreatitis [40,41]. Phar-macological treatment is often necessary to ensure that the pa-tients refrain from alcohol intake. Benzodiazepines and moodstabilizers such as carbamazepine are safe and efficacious intreating moderate symptoms of alcohol withdrawal [42]. Onlythree medications are used for treatment of alcohol dependence;naltrexone, acamprosate and disulfiram. Naltrexone has strongsupport in reducing relapse in alcoholics [43], while acamprosatehas shown efficacy in some [44] but not all trials [45]. Whiledisulfiram has been widely used, there is no clear clinical trial datasupporting positive outcomes [46].

Non-pharmacological treatments have also been widely used.Several psychosocial interventions have shown significant behav-ioral change in patients with alcohol dependence includingcognitive behavioral therapy [47,48]. Self-help organizations suchas Alcoholics Anonymous can also be helpful [49].

Tobacco: Several studies have shown that smoking tobacco,particularly cigarettes increased the risk for developing both acute[50,51] and chronic pancreatitis [52,53] and this relative risk isdose-dependent. More than 80% of patients with alcoholic chronicpancreatitis are smokers and smoking potentiates alcohol toxicityin dose-dependent way [53]. While cigarette smoking is oftenpresent in alcohol abuse, studies showing smoking as an inde-pendent predictive factor are emerging [50,54]. However, no studyhas evaluated the effect of smoking cessation on pain in patientswith CP.

Pharmacological treatment: Logically, smoking cessation shouldbe a strong recommendation. In a recent Cochrane review nicotinereplacement, bupropion, varenicline, and cytisine, another partialnicotine receptor agonist, had the greatest evidence for improvingthe chances of quitting [55].

Non-pharmacological treatment: Cognitive behavioral therapycombined with smoking cessation medications can be effective insmokers who are motivated to quit [56]. Mindfulness-based ther-apy may also help with recovery from smoking relapse [57].

Q5.Do enzymes and antioxidants influence pain in CP?

Pancreatic enzyme therapy with high protease content may betried as an initial treatment for pain relief in patients with CP.Furthermore; combination of antioxidants in sufficient dosagesshould be included in the armamentarium of pain treatments(Quality assessment: moderate; Recommendation: strong; Agree-ment: weak)

The pathophysiological basis of using pancreatic enzymes forpain in CP is related to the hypothesis that nutrients stimulate therelease of cholecystokinin releasing factor (CRF) from the duo-denum [58]. The CRF then releases cholecystokinin, which stimu-lates pancreatic secretion and this may increase intraductalpressure in patients who have ductal obstruction. Theoretically, thepancreatic enzymes degrade CRF thus limiting the release ofcholecystokinin and subsequently decrease pancreatic secretion.Six randomized clinical trials have been reported on the effect ofpancreatic enzymes in pain relief. In a review of these [59], painrelief using pancreatic enzymes as tablets was noted in two trials[60,61] and no benefit was noted in 4 trials that used acid-protectedcapsule form of enzymes [62e65]. The reason could be thatpancreatic enzymes were not released in the duodenum in theacid-protected form. If enzyme therapy is tried for pain relief, thepreparations should be uncoated, contain large amounts of pro-teases (>25,000 USP units per tablet) and be given in a dosage offour to eight tablets four times a day.

Antioxidants may also be helpful in pain treatment. Oxidativestress as a mechanism of inflammation in CP has been shown forthe past 30 years [66e70]. Consequently, antioxidant supplemen-tation has been used to ameliorate oxidative stress and relieve painin patients with CP. Recent meta-analyses of randomized controlledtrials have shown beneficial effect of antioxidants in patients withCP [71e73]. A combination of antioxidants (b-carotene, vitamin C,vitamin E, selenium, and methionine) has shown significant painrelief while studies with single antioxidant therapy showed nosignificant pain relief. A recent study has shown that a combinationof pregabalin and antioxidants resulted in benefit in those who hadrecurrence of pain after surgical and/or endoscopic therapy [74].

Q6. Which analgesics are recommended for pain in chronicpancreatitis?

Currently the standard guideline for analgesic therapy in CP followsthe principles of the “pain relief ladder” provided by the WorldHealth Organization (WHO) adjusted to the pain characteristics ofthis condition (Quality assessment: moderate; Recommendation:strong; Agreement: strong)

The standard guidelines for analgesic therapy in CP follow theprinciples of the “pain relief ladder” provided by the World HealthOrganization (WHO). This approach enables a simple stepwiseescalation of drugs with increasing analgesic potency (level I-III)until pain relief is obtained, with simultaneous monitoring andhandling of side effects [75].

Simple analgesics are used as a cornerstone in pain treatmentand paracetamol is the preferred level I drug due to its limited sideeffects. The non-steroidal anti-inflammatory drugs (NSAIDs)should in general be avoided due to their gastrointestinal toxicity[76]. This may especially be relevant in CP as patients are alreadypredisposed to peptic ulcers [77].

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Adjuvant analgesics are a heterogeneous group of drugs initiallydeveloped for indications other than pain and include antidepres-sants, anticonvulsants as well as anxiolytics (and spasmolytics inthe gut). Although adjuvant analgesics have been widely used inthe clinic to treat pain in CP, only pregabalin has been investigatedin this patient group andwas found to induce amoderate pain relief[78].

Anti-depressive drugs are widely used pain treatment in func-tional visceral pain disorders and although no data exist in CP, theirpositive effects in patients with neuropathic pain (thought to beprevalent in CP) makes them attractive [79]. It is, however, unclearif their effect is mediated through direct analgesic effects or indi-rectly by reducing anxiety and depression [80].

Opioid analgesics seem to be a necessary step to dampen pain inmany patients with CP, and it is mandatory that pancreatologistsunderstand the complexity of opioids [81]. Opioid based treat-ments are often associated with many severe adverse effects suchas constipation or opioid induced hyperalgesia [82,83]. Patients onlong-term opioid therapy must be kept under close clinical sur-veillance and it shall be stressed that only about 25% of patientsbenefit from treatment. Some drugs such as tramadol possessesboth a weak opioid agonist activity along with an effect onnoradrenaline and serotonin uptake [84]. Tramadol is often thepreferred level II analgesia and was shown to be superior tomorphine in patients with CP, with fewer gastrointestinal side ef-fects for the same level of analgesia [85]. Transdermal adminis-tration of opioids should be reserved to patients having troublewith tablet ingestion. There is marked inter-individual variability inresponsiveness to different opioids, and often a trial of an alter-native opioid is indicated [81,86].

In some patients unconventional treatment with drugs such asketamine is beneficial, but only in the hands of pain specialists.Somastotatin-analogue inhibits pancreatic secretion and maytheoretically alleviate pain through reduction of pancreatic ductalpressure. However, there are conflicting data about the efficacy.Other drugs including clonidine, benzodiazepines, anti-psychoticsor cannabinoids may also be beneficial in difficult cases.

In clinical practice pain treatment is mainly guided by evidencefrom somatic pain studies together with individual experience andtraditions. In Fig. 1 the pain treatment algorithm used at Centre forPancreatic Diseases, Aalborg University Hospital, Denmark isshown. This includes neurophysiological and psychological testing.For example segmental hyperalgesia of the epigastric skin area(pancreatic viscerotome) may predict the response to gabapenti-noids [87].

Q7. Is endoscopic therapy effective for pain treatment in CP?

The best candidates for successful treatment of painful CP withfirst-line endoscopic therapy are patients with distal obstruction ofthe main pancreatic duct (single stone and/or single stricture in thehead of the pancreas) and in the early stage of the disease. Endo-scopic therapy can be combined with Extracorporeal Shock WaveLithotripsy (ESWL) in the presence of large (>4 mm) obstructivestone(s) located in the pancreatic head, and with ductal stenting inthe presence of a dominant main pancreatic duct stricture thatinduces a markedly dilated duct. (Quality assessment: moderate;Recommendation: strong; Agreement: conditional)

Endoscopic therapy (ET) in painful CP is based on the rationalethat pain is related to an outflow obstruction of the main pancreaticduct (MPD) due to stricture(s) or pancreatic intraductal stone(s).

Endoscopic retrograde cholangio-pancreatography (ERCP) canachieve MPD drainage by sphincterotomy of the major and/or

minor papilla, by short-term stent placement or by pancreatic stoneextraction, usually after fragmentation with ESWL.

The effectiveness of ET is usually the result of these combinedprocedures; all of these are aimed to restore drainage of the MPD.With this approach about 60% experience complete or partial painrelief both in the short (<2 years) and long-term (>5 years) follow-up. However, the quality of evidence of reported results remainslow in most of these retrospective observational non-randomizedstudies (see Tables and studies in Appendix). Only two random-ized controlled trial (RCT) compared ET and surgery, and bothfavored surgery [88,89]. There were, however, several shortcom-ings. Among them was the low technical success rate [88] andsuboptimal procedures [89] compared with previous studies(Tables in Appendix). Contrary to surgery, ET is possible in patientswith risk factors such as older age and co-morbidities. Factorspredicting favorable clinical outcome after ET ± ESWL have beenidentified and are shown in Fig. 2 [90,91] (see also Tables inAppendix), and if clinical success can be obtained with � 5 endo-scopic interventions, the patient will probably achieve long-termfavorable outcome.

Q8. Is ESWL effective for pain treatment in CP?

In patients with uncomplicated painful calcified CP, ESWL alone is asafe and effective treatment. Best candidates for benefiting frominitial first-line ESWL are patients with obstructive calcifications, >4 mm confined to the head of pancreas. Combining systematicendoscopical therapy with ESWL adds to the cost of patient care, atthe same time not probably improving the outcome of pancreaticpain (Quality assessment: moderate, Recommendation strong;Agreement: conditional).

ESWL for pancreatic stones is indicated for patients with all ofthe following:

1. recurrent attacks of pancreatic pain2. moderate to marked changes in the pancreatic ductal system3. obstructing ductal stones (minimal diameter: 2e5 mm, calcified

or radiolucent) [92].

Regardless of the method of shock waves generation ESWLprovides high rates of stones fragmentation (average of 91% rangingfrom 54 to 100%) [92]. ESWL was proven useful for treating CPrelated pain in several meta-analyses [93,94] where the pooledproportion of patients with absence of pain at follow-up was about50% and narcotic use was decreased in 80%. In a prospective ran-domized study that compared ESWL alone with ESWL combinedwith endoscopy [95], there was no evidence that the combinationof endoscopy and ESWL was better than ESWL alone for paintreatment. Data regarding duct clearance have been somewhatconflicting ranging between similar for the procedures alone [96] toa better outcome for the combined procedures [97]. Factors asso-ciated with complete stone clearance included the presence of asingle stone vs. multiple stones [98,99], the absence of a MPDstricture [98] and a lower density of stones (<820 Hounsfield units)[100].

After treatment with ESWL (alone or combined with endoscopicdrainage), most of the patients who experienced pain relapsesdeveloped them during the first two years following treatment[90,95,101]. Pain relapse occurred significantly more frequently inpatients with incomplete removal of stones after the initial therapyand in those with a MPD stricture [98]. Other factors associatedwith long-term pain relief are short disease duration, low fre-quency of pain attacks before treatment, complete ductal stoneclearance, absence of MPD stricture and discontinuation of alcohol

Fig. 1. Suggested algorithm for pharmacological treatment (grey boxes) of pain in chronic pancreatitis. In most cases, combination therapies are necessary. Treatment withantidepressives is guided by psychological evaluation including assessment of catastrophizing, depression etc. In case gabapentinoids are considered we use evaluation of the ratiobetween segmental and generalised hyperalgesia (see text). Of note, treatment with gabapentinoids, TCA, SNRI (or SSRI in selected cases) should be titrated slowly until sufficienteffect or intolerable adverse effects occur. Treatment shall be individualised due to major differences in receptor properties and analgesic mechanisms between patients. NSAIDs arenormally not indicated and should be used carefully. Opioids shall be avoided if possible due to the major side effects on the gastrointestinal tract etc., but in severe pain they may be

A.M. Drewes et al. / Pancreatology 17 (2017) 720e731 725

A.M. Drewes et al. / Pancreatology 17 (2017) 720e731726

and tobacco [90,98,101,102].

Q9. Are other treatments (neurolytical, psychological, etc.)effective for pain management in CP?

Neurolytical interventions can be used in selected patients withpainful CP who have failed endoscopic and surgical treatment.Thoracoscopic splanchnic denervation is more effective regardinglong-term pain relief in patients who are not on chronic opioidtreatment. Behavioral interventions should be part of the multi-disciplinary approach in CP pain particularly when patientsexperience psychological impact of pain and quality of life hasdecreased. Early intervention in children may be particularlyimportant. (Quality assessment: low; Recommendation: strong;Agreement: conditional)

Neurolytic interventions: Celiac plexus blocks and splanchnicnerve ablation of patients with CP are generally advised when othermedical treatments for pain have failed. Several techniques forpercutaneous celiac plexus blockade have been described [103], butpain relief only lasts for short term with a risk for side effects suchas postural hypotension and diarrhea. Therefore celiac plexus blockis nowadays rarely applied in CP. Thoracoscopic splanchnicectomywas first described as a minimally invasive therapy for pain in 1994[104]; however, to date no RCT has been done. Preoperative opioiduse, duration of disease and pain seem to impair long term resultsprobably due to central sensitization [105].

There are only a few studies of spinal cord stimulation andtranscranial magnetic stimulation in chronic pancreatitis [106,107].Pain relief by spinal cord stimulation was achieved in 66% of pa-tients, but a drawback of the procedure is its invasiveness. Repet-itive TMS holds promise for treating depression in chronicpancreatitis patients with a possible concurrent pain relievingeffect.

Psychological/psychiatric interventions: There is a paucity ofstudies in CP, but in other chronic pain conditions psychologicalinterventions have been shown to be efficacious [108,109]. In-terventions include cognitive behavioral therapy, mindfulness ap-proaches, hypnosis etc. [110e113].

Children with CP represent an important subgroup who expe-riences frequent pancreatitis-related abdominal pain [114], butthere are no studies conducted to date. However, psychologicaltreatments for other forms of pediatric chronic pain have promisingeffects.

Q10. What is the optimal surgical approach to relieve pain inCP?

Depending on the morphological changes of the pancreas and painprocessing status a (partially) resection, decompression of thepancreatic duct or combined interventions can be performed toreduce pain. Long-term effects are variable, but success rates up to80% have been reported. The emerging role of total pancreatectomy

prescribed for limited periods and the physician shall always be aware of opioid induced b“Plus sign” indicate sufficient/satisfactory effect.“Minus sign” indicate insufficient effectESWL: extracorporalshock wave lithotrypsyPCM: paracetamolNSAID: non-steroidal anti-inflammatory drugsTCA: tricyclic antidepressivesSNRI: serotonin-noradrenalin reuptake inhibitorsSSRI: selective serotonin reuptake inhibitorsOIBD: opioid induced bowel dysfunction.

as initial surgical treatment looks promising but needs furtherinvestigation (Quality assessment: moderate; Recommendation:strong; Agreement: conditional)

Surgical options for pain are classified into three categories: a)decompression (focusing on ductal hypertension), b) resection(focusing on inflammatory masses and stones in the pancreatichead) and c) combined procedures. Although long-term results ofsurgery are promising, most of studies to date are observational oronly compare different invasive procedures. There are severalprocedures available dependent of the indication (see Appendix). Inrandomized controlled trials, tailored organ-sparing procedureshave been found to be superior to Whipple or the pylorus-preserving Whipple procedure in regard to pain relief (75%) andmorbidity (20%) [115,116]. An indication for total pancreatectomy(with/without islet autotransplantation) is to palliate pain espe-cially before diabetes mellitus has developed [117,118]. When cen-tral sensitization is present endoscopic and/or surgical therapy hasa higher risk of failure. Factors that are relevant in developingsensitization are duration of the disease, age, pain history andprevious invasive treatment [119]. Surgery has to be tailored to theneeds of patients and should be organ sparing in a high-volumecenter with expertise in pancreatic surgery.

Q11. When is the optimal time for surgery in painful CP?

Current evidence on the timing of surgery for painful CP suggests abeneficial role for early surgery, i.e. 1) within the first 2e3 yearsafter diagnosis or symptom onset, 2) for patients who had equal toor fewer than 5 endoscopic procedures, and 3) for patients whohave not yet required opioid analgesics for medical pain treatment(Quality assessment: low; Recommendation: weak; Agreement:strong).

Although there are no prospective controlled studies that spe-cifically addressed the timing of surgery for painful CP, increasingamount of evidence suggests that surgery should be consideredearly for better pain outcomes. In a systematic review that analyzedthe role of timing, it was found that early surgery was associatedwith a greater probability to attain postoperative pain relief [120].The optimal cutoff point for was found 26.5 months or less [121].Preoperative opioid use and 5 or more endoscopic interventionsalso seems to have negative influence [122,123]. In patients withobstruction of the duct system timing can be decisive for theoutcome.

Q 12. How to manage pain "relapse" after surgery orendoscopy for painful CP?

Current evidence suggests that the first step for the management ofpain relapse should be exclusion of obstructing stones or stricturedanastomosis via imaging, followed by a limited number endoscopicinterventions, and early consideration of re-surgery to achieve pain

owel dysfunction and hyperalgesia (narcotic bowel).

Fig. 2. The first step for the management of pain in patients with chronic pancreatitis should be to make a correct diagnosis based on clinical history and imaging procedures, and toexclude alternative diseases or complications that could induce pain not related to pancreatic ductal obstruction by stones and/or strictures.The second step should be to select the appropriate candidates for endoscopy (see the text for the definition of best candidates for endoscopical treatment with or without ESWL)and to treat such good candidates early in the disease course (within the first 2e3 years after symptom onset), with a limited number (< or ¼ 5) of endoscopic interventions. If nopersistent pain relief was obtained after a limited trial of endoscopic treatments ± ESWL, that means that other factors than increased pancreatic ductal pressure could be involvedin the pain syndrome and for these patients no further attempts at drainage should be proposed. In these patients or if the patient is not a candidate for endoscopy or in case oftechnical failure of endoscopy, medical treatment could be tried see e.g. Fig. 1. Surgery and alternative options could also be proposed if no persistent pain relief was obtained afterendoscopy, in case of limited effect of medical treatment.

A.M. Drewes et al. / Pancreatology 17 (2017) 720e731 727

control (Quality assessment: weak; Recommendation: strong;Agreement: weak).

After both surgery [124e126] and endoscopy [127], the long-term (5-year) pain free status is around 50e60%. Patients withpain relapse after endoscopical treatment may benefit of combinedantioxidant-pregabalin therapy [74]. There is lack of sufficient ev-idence for concrete recommendations for managing pain relapseafter surgery, but surgeons should consider that any kind of sub-sequent treatment may be subject to failure due to irreversibleneuropathic alterations [79,128]. In all cases, it is crucial to firstexclude more simple reasons for therapy failure such as obviousstricture of anastomosis, or obstructing stones in the pancreatic orbile duct [129]. Furthermore, it should be considered that a salvageoperation for pain relapse may end up in a total pancreatectomy.

Q13. What are the indications for referral to a specialist centerfor further investigation of pain?

All patients with presumed or established diagnosis of CP should beroutinely referred to specialist pancreatic centers for investigationand treatment of their disease (Quality assessment: moderate;Recommendation: strong; Agreement: strong).

Referral should be considered when non-specialist manage-ment is failing, chronic pain is poorly controlled, there is significantdistress, and/or where specific specialist intervention or assess-ment is considered. A systematic review of observational studies(although not in CP) concluded that a longer delay betweenspecialist referral and specialist consultation resulted in poorerhealth and pain management [130].

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://

dx.doi.org/10.1016/j.pan.2017.07.006.

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